Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been proposed that phorbol esters and the Ca2+ ionophore A23187 are effective comitogens for some species of lymphocytes because together they mimic the normal secondary signals for cell activation by mitogens that cause phosphatidylinositol 4,5-bisphosphate (PtdInsP2) breakdown (e.g., anti-TCR and anti-Thy-1 antibodies and Con A). To test whether activation of protein kinase C and an increase in [Ca2+]i account for the activation of the mitogenic pathway in murine thymocytes by the mitogens that cause PtdInsP2 breakdown, the two-dimensional phosphorylation patterns generated by the three classes of mitogens (protein kinase C activator, Ca2+ ionophore, and activator of PtdInsP2 breakdown) and by activators of cAMP-dependent kinases have been compared. From the phosphorylation patterns, by which each mitogen could be distinguished reproducibly, it was concluded that: 1) The phosphorylation patterns generated by the mitogens that activate PtdInsP2 breakdown are only slightly affected by the removal of extracellular Ca2+ under conditions that abolish the normal rise in [Ca2+]i and do not therefore depend on the activation of Ca2(+)-dependent protein kinases. In contrast, the phosphorylation pattern generated by A23187 is totally dependent on extracellular Ca2+. 2) Neither A23187 nor the mitogens that activate PtdInsP2 breakdown nor activators of cAMP-dependent kinases caused significant activation of protein kinase C assayed by phosphorylation of the diagnostic proteins 80b and 78a. Consistent with this conclusion, only the phorbol esters or oleoyl acyl glycerol caused translocation of protein kinase C activity from the cytosolic to the membrane fraction. 3) Neither A23187 nor the mitogens that cause PtdInsP2 breakdown activated cAMP-dependent kinases. Taken together the data imply that the mitogens that cause PtdInsP2 breakdown must generate an additional, independent primary mitogenic signal. It is suggested that this signal may be the activation of tyrosine kinases (e.g., p56lck) via the TCR and working hypotheses for effective combinations of primary mitogenic signals that will activate DNA synthesis are developed.
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PMID:Analysis of the primary signals required for activation of the mitogenic pathway in murine thymocytes from protein phosphorylation patterns. 221 54

p56lck is a member of the src family of tyrosine kinases that is expressed almost exclusively in lymphocytes. Previous studies have shown that treatment of T cells with activators of protein kinase C induces serine phosphorylation of p56lck. We show here that treatment of Jurkat cells with 12-O-tetradecanoyl phorbol-13-acetate also induces threonine phosphorylation of p56lck. Chymotryptic mapping shows that at least three sites in p56lck undergo phosphorylation in TPA-treated Jurkat cells. Cyanogen bromide cleavage analysis demonstrates that these new phosphorylation sites are located in an amino-terminal 32 kDa fragment containing amino acid residues 14-261.
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PMID:Analysis of the sites in p56lck whose phosphorylation is induced by tetradecanoyl phorbol acetate. 235 19

The protein tyrosine kinase p56lck is implicated in the control of lymphocyte growth by virtue of its overexpression in some lymphoid malignancies and its transforming activity in heterologous systems. Previous studies have demonstrated that levels of lck mRNA and of p56lck decline rapidly after T cell activation. The disappearance of p56lck results primarily from post-translational conversion of p56lck to more slowly migrating forms with apparent sizes of approximately 60 kDa. This modification can be provoked by treatment of lymphocytes with PMA, and has been associated with increased serine phosphorylation of the p56lck molecule. Here we demonstrate that conversion of p56lck to p60lck is a feature of the physiologic activation of T lymphocytes by antigen-presenting cells. In addition, we show that the PMA-induced modification of p56lck proceeds via a mechanism distinct from conventional protein kinase C activation. The rapid conversion of p56lck to p60lck after antigenic stimulation is consistent with the view that this membrane-associated protein tyrosine kinase regulates some aspects of the lymphocyte activation sequence.
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PMID:Lymphocyte activation provokes modification of a lymphocyte-specific protein tyrosine kinase (p56lck). 278 63

The CD4 and CD8 T cell receptor accessory molecules can both be isolated from T lymphocytes in association with p56lck, a membrane-associated, cytoplasmic tyrosine protein kinase that is expressed exclusively in lymphoid cells. The enzymatic activity of p56lck may therefore be regulated by CD4 and CD8 and be important in antigen-induced T cell activation. Exposure of human T cells and some mouse T cells to the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate (TPA), an activator of protein kinase C, caused the dissociation of p56lck and CD4. Activation of protein kinase C may therefore interrupt regulation of p56lck by CD4 and alter the ability of p56lck to interact with polypeptide substrates. In contrast, exposure of cells to TPA did not cause dissociation of p56lck and CD8. Regulation of p56lck by CD4 may therefore differ from regulation by CD8.
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PMID:Activators of protein kinase C induce dissociation of CD4, but not CD8, from p56lck. 278 34

We have found in different human cells of lymphoid and non-lymphoid origin that the 56 kilodalton (kDa) lck protein is rapidly converted to a product migrating at approximately 60 kDa (designated p60lck) in response to the phorbol ester 4 alpha-phorbol 12 beta-myristate (PMA) as well as the diacylglycerol analogue 1,2-dioctanoyl-sn-glycerol (diC8). This conversion is associated with an increase in serine phosphorylation within the amino-terminal 18 kDa portion of the lck protein. The serine phosphorylation modification and diminished electrophoretic mobility of the lck protein appear to be completely reversible within 60 min following treatment with diC8. The changes in p56lck phosphorylation and gel mobility in response to activators of protein kinase C are also associated with a small but reproducible decrease in the ability of the lck protein to be phosphorylated in immune complex kinase assays. While these alterations of the lck gene product may play an important role in antigen-mediated activation of T-lymphocytes, we demonstrated that they can also be induced independently of T-cell activation suggesting that they are not necessarily implicative of this process.
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PMID:Post-translational alterations of the tyrosine kinase p56lck in response to activators of protein kinase C. 304 47

The lymphocyte-specific tyrosine protein kinase p56lck is abundantly expressed in L3T4+ (CD4+) and Lyt-2+ (CD8+) T-lymphocytes, where it is predominantly phosphorylated in vivo on the carboxy-terminal tyrosine residue 505 (Y-505). Upon exposure to activating signals (mitogenic lectins, antibodies to the T-cell receptor), the p56lck expressed in normal cloned murine T-cells is modified into a product which migrates at approximately 59 kilodaltons on sodium dodecyl sulfate-polyacrylamide gels and which possesses several amino-terminal serine phosphorylations. The changes in both mobility and amino-terminal phosphorylation can be reproduced by known activators of protein kinase C (4 alpha-phorbol 12 beta-myristate, dioctanoylglycerol), suggesting that this signal transduction pathway (or related pathways) mediates at least part of these events. Interestingly, agents raising intracellular calcium (such as A23187) cause the appearance of several of these amino-terminal phosphorylation changes but do not cause the pronounced shift in electrophoretic mobility. These data suggest that at least two serine kinase systems are implicated in the alterations of p56lck associated with T-cell activation and that the lck gene product plays a critical role in normal T-cell physiology.
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PMID:Alterations of the lymphocyte-specific protein tyrosine kinase (p56lck) during T-cell activation. 314 89

As presently reported, both ionizing radiation and engagement of the CD19 receptor are capable of inducing apoptosis in B-lineage acute lymphoblastic leukemia (ALL) cells. In both instances, activation of tyrosine kinases appears to be a proximal and mandatory step, since it can be prevented by the tyrosine kinase inhibitor genistein. This common biochemical signaling pathway involves the rapid activation of the Src family tyrosine kinase LCK (p56lck), which is physically associated with the CD19 receptor, and enhanced tyrosine phosphorylation of multiple substrates leading to stimulation of phosphoinositide turnover, and activation of protein kinase C. Importantly, engagement of the CD19 receptor promoted radiation-induced apoptosis in radiation-resistant B-lineage ALL cells in a cell type-specific fashion. Our results prompt the hypothesis that clonogenic B-lineage ALL blasts with an inherent or acquired resistance to radiation could be radiosensitized in clinical settings using anti-CD19 MoAb B43 or its homoconjugate as adjuncts.
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PMID:Engagement of the CD19 receptor on human B-lineage leukemia cells activates LCK tyrosine kinase and facilitates radiation-induced apoptosis. 750 28

We recently identified Vav as a Ras-activating guanine nucleotide exchange factor (GEF) stimulated by a T-cell antigen receptor-coupled protein tyrosine kinase (PTK). Here, we describe a novel, protein kinase-independent alternative pathway of Vav activation. Phorbol ester, 1,2-diacylglycerol, or ceramide treatment of intact T cells, Vav immunoprecipitates, or partially purified Vav generated by in vitro translation or COS-1 cell transfection stimulated the Ras exchange activity of Vav in the absence of detectable tyrosine phosphorylation. GEF activity of gel-purified Vav was similarly stimulated by phorbol myristate acetate (PMA). Stimulation was resistant to PTK and protein kinase C inhibitors but was blocked by calphostin, a PMA and diacylglycerol antagonist. In vitro-translated Vav lacking its cysteine-rich domain, or mutated at a single cysteine residue within this domain (C528A), was not stimulated by PMA but was fully activated by p56lck. This correlated with increased binding of radiolabeled phorbol ester to COS-1 cells expressing wild-type, but not C528A-mutated, Vav. Thus, Vav itself is a PMA-binding and -activated Ras GEF. Recombinant interleukin-1 alpha stimulated Vav via this pathway, suggesting that diglyceride-mediated Vav activation may couple PTK-independent receptors which stimulate production of lipid second messengers to Ras in hematopoietic cells.
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PMID:Direct stimulation of Vav guanine nucleotide exchange activity for Ras by phorbol esters and diglycerides. 751 72

The glycosylphosphatidylinositol (GPI)-anchored CD59 protein (human protectin) protects cells against complement-induced lysis, binds to CD2 and also transduces activation signals within T cells. We have further examined the biochemical signals transduced by CD59 and addressed its role in regard to the CD3-mediated signaling cascade. We show here that CD59 cross-linking induces a time-dependent activation of p56lck and of p70zap (ZAP-70) in CD3-positive Jurkat cells, leading to the stimulation of the T cell receptor zeta/ZAP-70 signaling cascade and interleukin-2 (IL-2) synthesis. Cross-linking of CD59 on peripheral T cells and thymocytes induces tyrosine phosphorylations identical to those seen in Jurkat cells and this is followed by lymphokine production and proliferation. In contrast, only activation of CD59-associated p56lck occurs in CD3-negative Jurkat cells, while IL-2 production is impaired, consistent with the lack of ZAP-70 tyrosine phosphorylation observed in these cells. CD59 triggers activation events even in the absence of CD3/T cell receptor expression in Jurkat cells. CD59 cross-linking synergizes with sub-optimal doses of phorbol ester for activation of the protein kinase C and of the p42mapk, as shown by in vitro phosphorylation of histone HIIIS and myelin basic protein, respectively, and leads to CD25 but not CD69 expression. In conclusion, at least two signaling pathways are triggered through CD59, the first one involving ZAP-70 activation and leading to IL-2 secretion and a second pathway observed in the absence of ZAP-70 activation leading to CD25 expression. These two pathways are likely to be involved in the modulation of T cell activation by CD59 protein.
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PMID:The glycosylphosphatidylinositol-anchored CD59 protein stimulates both T cell receptor zeta/ZAP-70-dependent and -independent signaling pathways in T cells. 754 90

The CD4 coreceptor interacts with non-polymorphic regions of major histocompatibility complex class II molecules on antigen-presenting cells and contributes to T cell activation. We have investigated the effect of CD4 triggering on T cell activating signals in a lymphoma model using monoclonal antibodies (mAb) which recognize different CD4 epitopes. We demonstrate that CD4 triggering delivers signals capable of activating the NF-AT transcription factor which is required for interleukin-2 gene expression. Whereas different anti-CD4 mAb or HIV-1 gp120 could all trigger activation of the protein tyrosine kinases p56lck and p59fyn and phosphorylation of the Shc adaptor protein, which mediates signals to Ras, they differed significantly in their ability to activate NF-AT. Lack of full activation of NF-AT could be correlated to a dramatically reduced capacity to induce calcium flux and could be complemented with a calcium ionophore. The results identify functionally distinct epitopes on the CD4 coreceptor involved in activation of the Ras/protein kinase C and calcium pathways.
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PMID:Distinct signaling properties identify functionally different CD4 epitopes. 754 91


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